Amyloid-PET predicts inhibition of de novo plaque formation upon chronic γ-secretase modulator treatment
| Autor: | Franz-Josef Gildehaus, Matthias Brendel, Janette Carlsen, Anna Jaworska, Peter Bartenstein, Christian Haass, Christina Rötzer, Thomas Luebbers, Johannes Trambauer, Harald Steiner, Johan Bylund, Paul Cumming, Karlheinz Baumann, Jochen Herms, Axel Rominger |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Cerebellum
Pathology Plaque Amyloid antagonists & inhibitors [Amyloid Precursor Protein Secretases] pathology [Alzheimer Disease] Mice Amyloid beta-Protein Precursor 0302 clinical medicine metabolism [Amyloid beta-Protein Precursor] Stilbenes drug therapy [Plaque Amyloid] drug therapy [Alzheimer Disease] Longitudinal Studies 0303 health sciences Aniline Compounds methods [Positron-Emission Tomography] chemical synthesis [Aniline Compounds] 3. Good health Psychiatry and Mental health medicine.anatomical_structure Original Article Female enzymology [Plaque Amyloid] Genetically modified mouse medicine.medical_specialty pharmacology [Stilbenes] Transgene Mice Transgenic Biology 03 medical and health sciences Cellular and Molecular Neuroscience Text mining Alzheimer Disease In vivo Internal medicine medicine Potency Distribution (pharmacology) Animals chemical synthesis [Stilbenes] ddc:610 4-(N-methylamino)-4'-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)stilbene Molecular Biology 030304 developmental biology business.industry therapy [Cerebral Amyloid Angiopathy] In vitro metabolism [Amyloid Precursor Protein Secretases] metabolism [Plaque Amyloid] pharmacology [Aniline Compounds] Mice Inbred C57BL Cerebral Amyloid Angiopathy Disease Models Animal Endocrinology Positron-Emission Tomography Case-Control Studies diagnostic imaging [Plaque Amyloid] Amyloid Precursor Protein Secretases business 030217 neurology & neurosurgery |
| Zdroj: | Molecular psychiatry 20(10), 1179-1187 (2015). doi:10.1038/mp.2015.74 Molecular Psychiatry |
| DOI: | 10.1038/mp.2015.74 |
| Popis: | In a positron-emission tomography (PET) study with the β-amyloid (Aβ) tracer [(18)F]-florbetaben, we previously showed that Aβ deposition in transgenic mice expressing Swedish mutant APP (APP-Swe) mice can be tracked in vivo. γ-Secretase modulators (GSMs) are promising therapeutic agents by reducing generation of the aggregation prone Aβ42 species without blocking general γ-secretase activity. We now aimed to investigate the effects of a novel GSM [8-(4-Fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine (RO5506284) displaying high potency in vitro and in vivo on amyloid plaque burden and used longitudinal Aβ-microPET to trace individual animals. Female transgenic (TG) APP-Swe mice aged 12 months (m) were assigned to vehicle (TG-VEH, n=12) and treatment groups (TG-GSM, n=12), which received daily RO5506284 (30 mg kg(-1)) treatment for 6 months. A total of 131 Aβ-PET recordings were acquired at baseline (12 months), follow-up 1 (16 months) and follow-up 2 (18 months, termination scan), whereupon histological and biochemical analyses of Aβ were performed. We analyzed the PET data as VOI-based cortical standard-uptake-value ratios (SUVR), using cerebellum as reference region. Individual plaque load assessed by PET remained nearly constant in the TG-GSM group during 6 months of RO5506284 treatment, whereas it increased progressively in the TG-VEH group. Baseline SUVR in TG-GSM mice correlated with Δ%-SUVR, indicating individual response prediction. Insoluble Aβ42 was reduced by 56% in the TG-GSM versus the TG-VEH group relative to the individual baseline plaque load estimates. Furthermore, plaque size histograms showed differing distribution between groups of TG mice, with fewer small plaques in TG-GSM animals. Taken together, in the first Aβ-PET study monitoring prolonged treatment with a potent GSM in an AD mouse model, we found clear attenuation of de novo amyloidogenesis. Moreover, longitudinal PET allows non-invasive assessment of individual plaque-load kinetics, thereby accommodating inter-animal variations. |
| Databáze: | OpenAIRE |
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